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A. Soltermann



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    P1.09 - Mesothelioma (ID 695)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Mesothelioma
    • Presentations: 1
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      P1.09-007 - Targeting MET/TAM Receptors in Mesothelioma: Are Multi-TKIs Superior to Specific TKI? (ID 9959)

      09:30 - 09:30  |  Author(s): A. Soltermann

      • Abstract

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer associated with exposure to asbestos, and most patients die within 24 months of diagnosis. There is an urgent need to identify new therapies for treating MPM patients. Targeting “addicted” receptor tyrosine kinase (RTK) signalling networks has become a critical therapy option in cancer therapy. RTK hetero-dimerization may however, be a key element in the development of resistance to such therapy. As such Tyrosine kinase inhibitors (TKIs) with the ability to target multiple receptors may have superior efficacy to those targeting individual receptors. We and others have identified c-MET, MST1R (also known as RON), Axl and Tyro3 as RTKs frequently overexpressed and activated in MPM, making these attractive candidate targets. Several agents have been developed which target these. LCRF0004 specifically targets MST1R, whereas BMS-777607, RXDX-106 or Merestinib (LY2801653) are orally bioavailable small molecule inhibitors which inhibit c-MET, MST1R, Axl and Tyro3 at nM concentrations. These drugs may therefore have clinical utility in the treatment/management of MPM.

      Method:
      Expression of RON/MET/TAM and associated ligands were assessed in a cohort of patient samples and MPM cell lines comprising benign, epithelial, biphasic, and sarcomatoid histologies. In vitro and in vivo experiments were undertaken to determine the efficacy of single and multi RTK targeting agents (LCRF0004, RXDX-106, BMS-777607). The effects of LCRF0004 and BMS-777607 were subsequently examined in an in vivo SQ xenograft tumour model.

      Result:
      mRNA expression of the RON/MET/TAM family and associated ligands (MSP, GAS6) was detected in a large panel of normal pleural and MPM cell lines. In a cohort of patient samples, mRNA levels of c-MET, Axl, Tyro3 and various isoforms of MST1R (flRON, sfRON, t-ΔRON) and MSP but not Gas6 or MERTK were increased in tumours compared with benign pleural samples (p<0.05). No MET Exon 14 skipping mutations were detected. RTK targeting agents displayed in vitro efficacy in terms of reduced proliferation. In vivo, the multi-target TKI (BMS-777607) demonstrated superior anti-tumour activity compared with LCRF0004 (MST1R specific compound). IHC analysis of the xenograft tumours showed high cytoplasmic expression of Vimentin, Cytokeratin and Calretinin, with significant necrosis in many.

      Conclusion:
      Our data suggests that a multi-TKI, targeting the RON/MET/TAM signalling network, is superior to selective RTK inhibition as an interventional strategy in MPM.

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    P1.17 - Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies (ID 703)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      P1.17-016 - Immunohistochemical Markers as Prognostic Factors in Malignant Thymic Epithelial Tumors (ID 10338)

      09:30 - 09:30  |  Author(s): A. Soltermann

      • Abstract

      Background:
      Thymic epithelial tumors (TET) are rare neoplasms with inconsistent treatment strategies. When researching for molecular pathways to find new therapies, the correlation between specific molecular markers and outcome has been rarely investigated. The aim of this study was to investigate the correlation between survival, metastatic potential and invasiveness of aggressive subtypes of TET and immunohistochemical markers.

      Method:
      We performed retrospective analysis on patients with WHO type B2/B3 mixed type thymoma (MT), thymoma type B3 (B3) and thymic carcinoma (TC) who underwent surgery from 1998 to 2013. Overall survival (OS), disease-free survival (DFS), progression-free survival (PFS) and metastasis-free survival (MFS) were examined. Tumor specimens were stained using a tissue microarray (TMA) (CD117, CD5, p63, p40, p21, p27, p53, Bcl-2, Ki67, podoplanin, synaptophysin, PTEN and Pax8). Invasive behavior of primary tumors and the presence of extrathoracic metastases were assessed.

      Result:
      In 23 patients included into this study (four MT, ten B3, nine TC), we found (I) p21 expression in the cytoplasm significantly correlated with a decrease of OS (P=0.016), PFS (P=0.034) and MFS (P=0.005); (II) MFS was significantly shorter when the combination of p21-low p27-low p53-high was present (P=0.029); and (III) nuclear p27 (P=0.042), Ki-67 (P=0.024) and podoplanin (P=0.05) expression correlated with the presence of extrathoracic metastases.

      Conclusion:
      The main finding of this study is that cytoplasmic p21 expression negatively influences the outcome of malignant TETs and correlates with metastatic activity. Additionally, selected immunohistochemical markers correlate with the distant metastatic potential of TETs. These results may contribute to the stratification of diagnosis and improvement of treatment strategies for thymic malignancies. ​

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    P2.02 - Biology/Pathology (ID 616)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P2.02-036 - The Expression Pattern of CD26/DPP4 in Human Lung Cancer (ID 9319)

      09:30 - 09:30  |  Author(s): A. Soltermann

      • Abstract

      Background:
      Lung cancer is the leading cause of death among cancers. Despite improved surgical and novel radiation improvements, the overall prognosis remains poor. CD26/dipeptidyl peptidase 4 (DPP4) is a ubiquitously expressed transmembrane exopeptidase on the cell surfaces of many different cells including malignancies of breast, colon, and mesothelioma. Phase I data in mesothelioma with a specific antibody showed tolerability in mesothelioma patients.Our group found previously that the activity of CD26/DPP4 of lung adenocarcinoma (Adeno-CA) patients is four times higher than in normal tissue and the inhibition of CD26/DPP4 decreased the growth of lung tumors in experimental models. These data prompted us to analyze the expression of CD26/DPP4 in samples from lung cancer patients to unravel the role of CD26/DPP4 as a biomarker for lung cancer and a target for inhibition to reduce lung cancer burden. burden.

      Method:
      To identify CD26/DPP4 by immunohistochemistry (IHC), we tested four antibodies from Abcam, R/D systems, and Cell signaling technology on multi-organ tissue micro array (TMA) and human lung Adeno-CA cell lines (A549, H460, Gon8, Mai9) derived from advanced stage (IV) of human Adeno-CA. We selected the antibody from Cell signaling technology against CD26/DPP4. For the analysis of CD26/DPP4 by IHC in lung cancer samples, TMAs constructed from non-small cell lung cancer patients were used. The cohort consisted of 475 patients (Adeno-CA: 223; Squamous carcinoma: 252). The intensity of the staining was scored from 0 to 3 in a blinded manner. To quantify CD26/DPP4 in the supernatant of human lung Adeno-CA cell lines in vitro, ELISA was performed.

      Result:
      IHC scores revealed that Adeno-CA expresses significantly more CD26/DPP4 compared to squamous carcinoma (p<0.0001). Consistent with our previous findings, early stage cancer (IA) scores significantly higher than other stages IIB (p=0.0012), IIIA (p=0.0019), and IV (p=0.02) among Adeno-CA samples. We could not find CD26/DPP4 expression on human Adeno-CA cell lines by IHC, but the secretion of the protein in supernatant stays high (A549: 20pg/ml; H460: 161pg/ml; Gon8: 74pg/ml; Mai9: 648pg/ml).

      Conclusion:
      CD26/DPP4 expression was significantly higher at early stages of Adeno-CA samples when compared to advanced stages, supporting our previous findings. From the human cell line data, we suggest that advanced cancer secretes CD26/DPP4 more actively than early stage cancers. CD26/DPP4 seems to be a substantial target for inhibition of human Adeno-CA.